In this competing renewal application currently in its 9th year of funding we propose to expand our findings of the last funding period to explore new dimensions of polydrug abuse using both electrophysiological and behavioral instruments. Seven specific experiments are planned to address the following: 1) Whether pretreatment with ethanol or marihuana alters the electrophysiological and behavioral components of cocaine-seeking behavior. 2) Whether the presentation of cocaine-related cues to cocaine-dependent subjects elicits changes in brain electrical activity and behavior that are similar to those observed during cocaine-seeking behavior. A related experiment will measure whether tobacco-related cues elicit conditioned responses in cocaine freebase smokers. 3) Whether tobacco-related cues elicit electrophysiological and behavioral responses in tobacco-dependent subjects that are similar to those observed in cocaine-dependent subjects who are exposed to cocaine-related cues. 4) Whether cocaine alone, ethanol alone or cocaine/ethanol combinations disrupt sleep architecture and continuity. A related study will evaluate chronic cocaine freebase smokers for primary sleep disorders. 5) Whether the acute effects of cocaine are different in heavy tobacco smokers as compared to non smokers. Whether pretreatment with a nicotine transdermal patch alters cocaine's acute effects and cocaine self-administration using a choice procedure. 6) Whether ethanol, cocaine or ethano/cocaine combinations increase aggressive behavior and whether estrogen or marihuana pretreatment attenuates the resultant aggressive behavior. 7) What are the neuroanatomical profiles of the alterations in EEG alpha activity and P3 event-related potentials (ERP) associated with drug-seeking behavioral and drug-related cue exposure? Both male and female healthy volunteers will serve as subjects; cocaine- dependent subjects will be recruited from our outpatient treatment program for the cocaine cue studies. The major dependent variables will be brain electrical activity, P3 ERPs, heart rate, skin temperature, subjective reports of intoxication, Addiction Research Inventory scales, visual analog scales, instrumental joystick responding, Point Subtraction Aggression Paradigm for aggressive behavior and reaction time performance. Frequent blood samples will be collected to quantify potential changes in pharmacokinetic parameters. These studies will expand the scope of our understanding of the dynamics of polydrug abuse by examining the factors that contribute to multiple drug use with tools that are sensitive to the subtle but reproducible changes in brain activity and behavior associated with drug reinforcement. Our observations that tobacco and cocaine share many common features helped to shape our current strategy of evaluating pharmacotherapies that is a departure from the currently popular theme of studying drugs that alter dopamine and/or serotonin systems. It is anticipated that information obtained in the present series of experiments will be useful in understanding the mechanism of polydrug abuse, identifying factors that support polydrug abuse and to designing completely new strategies for treating polydrug abuse and dependence.